Phase I Trial of MK-0752 in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study
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Purpose: To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. Patients and Methods: MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m 2. The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. Results: Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m 2/dose. At 260 mg/m 2/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non–dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m 2; apparent volume of distribution, 7.36 (24%) L/m 2; and k a, 0.358 (99%) hr−1. Conclusion: MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m 2/dose once daily.
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MK-0752 reduces the generation of amyloid-β after crossing the blood-brain barrier in vivo.
“MK-0752 reduces the generation of amyloid-β after crossing the BBB in vivo42,43.”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [43]
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- Authors
- Fouladi, M., Stewart, C. F., Olson, J., Wagner, L. M., Onar-Thomas, A., Kocak, M., Packer, R. J., Goldman, S., Gururangan, S., Gajjar, A., Demuth, T., Kun, L. E., Boyett, J. M., & Gilbertson, R. J.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Maryam Fouladi and Lars M. Wagner, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Clinton F. Stewart, Arzu Onar-Thomas, Mehmet Kocak, Amar Gajjar, Larry E. Kun, James M. Boyett, and Richard J. Gilbertson, St Jude Children's Research Hospital, Memphis, TN; James Olson, Seattle Children's Hospital, Seattle, WA; Roger J. Packer, Children's National Medical Center, Washington, DC; Stewart Goldman, Children's Memorial Hospital, Chicago, IL; Sridharan Gururangan, Duke University Medical Center,...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2011-09-10
- Volume
- 29
- Issue
- 26
- Pages
- 3529-3534
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC3179253
- OpenAlex
- W2099293048
- Cited by
- 164
- References
- 47
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 11 · 2021: 7 · 2020: 7 · 2019: 2 · 2018: 10 · 2017: 12 · 2016: 7 · 2015: 26 · 2014: 21 · 2013: 19 · 2012: 23
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (U01 CA81457, U01CA081457)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- gamma-secretase inhibitors, Notch signaling, pediatric brain tumors, maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, brainstem glioma, ependymoma, medulloblastoma, atypical teratoid/rhabdoid tumor, choroid plexus carcinoma
- MeSH terms
- Transcription Factor HES-1, Adolescent, Antineoplastic Agents, Benzene Derivatives, Child, Child, Preschool, Female, Humans, Male, Propionates, Recurrence, Repressor Proteins, Sulfones, Central Nervous System Neoplasms, Homeodomain Proteins, Maximum Tolerated Dose, Basic Helix-Loop-Helix Proteins, Receptor, Notch1, Amyloid Precursor Protein Secretases, Drug-Related Side Effects and Adverse Reactions
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